Cats are uniquely poised to serve as reservoirs and potential `mixing vessels'for influenza viruses given their interaction within the environment of humans, wildlife, birds, and farm animals. However, cats have been overlooked as a potential reservoir because early experimental infections did not result in clinical disease. Yet, despite the absence of clinical disease, these same studies demonstrated that cats still shed influenza virus in respiratory excretions. Newer studies on highly pathogenic avian influenza suggest that cats may also shed virus by fecal excretion and become infected by oral as well as respiratory exposure. Whether low pathogenicity subtypes can be transmitted horizontally in cats and/or shed in the feces has not been evaluated. Taken together, these findings suggest that cats may be an asymptomatic and previously uncharacterized carrier population for influenza viruses. The goal of this proposal is to develop a model of influenza infection of cats with relevant viral strains to better understand the role that cats may play in influenza outbreaks. We will systematically define the transmission, shedding, and immunopathogenesis of common influenza viruses in cats. We hypothesize that domestic cats can be infected with strains of influenza that are relevant in the United States and serve as a viral reservoir. We will test this through four specific aims. We will (1) identify the range of influenza viruses that can infect domestic cats. Once we have identified 1-2 different strains that readily infect domestic cats, we will ask the following questions: (2) Does the route of infection alter the efficiency of transmission, early pathogenesis, immune responses, and patterns of shedding? (3) Can influenza strains that infect cats can be transmitted horizontally from cat to cat? And (4) What are the genetic parameters important for efficient transmission of avian influenza strains into cats. PUBLIC HEALTH RELEVANCE: Reports of experimental and naturally acquired influenza virus infections indicate that cats can be infected with avian influenza viruses (H5N1 and H7N3), at least one human influenza virus (H3N2), and influenza virus from a non-human mammal (H7N7). Furthermore, even asymptomatic cats shed infectious virus and, at least highly pathogenic strains can be transmitted from cat-to-cat. Additional information regarding the transmission, pathogenesis, and routes of shedding of endemic influenza viruses as well as those with potential for interspecies transmission is necessary to identify whether cats serve as a reservoir for influenza transmission, outbreaks, and potential interspecies mixing.